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Development of a preventive vaccine against human immunodeficiency virus type 1 (HIV-1) is urgently needed to control the spread of the virus worldwide. Although the immunological parameters that correlate with protective immunity against natural infection with HIV-1 are not fully known, it is assumed that a preventive vaccine must elicit potent, broadly reactive immunity against divergent strains of HIV-1 (25, 36, 42). Several recent studies have demonstrated that induction of virus-specific T-cell responses can confer protective immunity in nonhuman primate models, and these responses may also play a role in controlling HIV-1 replication in humans (6, 18, 19, 31, 33, 34, 38, 45, 48). Vaccine constructs containing viral env genes, in addition to gag and pol, have been shown to effectively control replication of challenge viruses (2, 5, 10), suggesting that neutralizing antibody (NAb) responses might also contribute to protection against pathogenic infection or disease progression. Passive transfer of serum immunoglobulin from chimpanzees experimentally infected with several different HIV-1 isolates has been shown to block the establishment of a simian immunodeficiency virus (SIV)-HIV chimeric simian-human immunodeficiency virus (SHIV) infection in pig-tailed macaques (37, 46). It is not known, however, whether vaccines that actively elicit a potent NAb response can provide protection in nonhuman primates challenged with SHIV. Previously, we demonstrated that recombinant Mycobacterium bovis bacillus Calmette-Guerin (rBCG), which secretes a chimeric protein consisting of the V3-neutralizing epitope of HIV-1 and α-antigen (rBCG Env V3), can induce HIV-1-specific NAb in a small-animal model (9, 15, 16). BCG was selected as a vaccine vehicle because it has several characteristics that are considered efficacious for developing a candidate HIV-1 vaccine (1, 49), including the ability to induce long-lasting immune responses (7). It is generally accepted that a candidate vaccine against HIV-1 must also be easily administered and affordable in developing countries, and it must be compatible with other commonly administered vaccines (35). If effective, a BCG-based recombinant HIV-1 (rBCG-HIV-1) vaccine would fulfill many of these critical requirements. Results using other vaccine modalities, in particular, live attenuated SIV vaccines, have raised concerns about the potential for reversion to pathogenicity (3, 4), suggesting that many SIV strains may be potentially virulent. In this study, we used two distinct strains of challenge virus: SHIV-MN (29), which contains V3 sequences homologous to rBCG Env V3, and SHIV-89.6PD (12, 20, 28, 41), which is heterologous in the V3 region and highly pathogenic. We examined whether vaccination with rBCG Env V3 could effectively elicit NAb responses in rhesus macaques and whether it might effectively induce protective immunity against challenge with either SHIV-MN or SHIV-89.6PD.